Diarylalkyl piperidines useful as multi-drug resistant tumor agents

ABSTRACT

Diarylalkyl piperidines of formula (1) ##STR1## reverse drug resistance in multi-drug resistant tumors. These compounds apparently function by inhibiting a p-glycoprotein pump which becomes activated in late stage tumor development and which is inherently present in tumors from certain origins.

The present application is a 371 of PCT/US93/12300 filed Dec. 17, 1993which is a continuation of application Ser. No. 08/111,027, filed Aug.24, 1993, now abandoned, which is a continuation of application Ser. No.08/006,569, filed Jan. 21, 1993, now abandoned.

BACKGROUND OF THE INVENTION

Effective tumor treatment is frequently thwarted by the lack ofsensitivity of certain tumors to standard chemotherapeutic agents(intrinsic resistance) or by the ability of certain tumors to develop alack of chemotherapeutic sensitivity during the course of treatment(acquired or extrinsic resistance). The cause of these phenomena hasbeen linked to the existence of an energy dependent efflux pump whichacts to remove the chemotherapeutic agent from the target cell. The pumpconsists of the P-glycoprotein found as a constituent of cell membrane,and it has been suggested that the normal function of the P-glycoproteinis to remove toxins from within the cell. This theory is supported bythe observation that P-glycoprotein is found as a cell membraneconstituent in cells of liver, kidney, colon, and jejunum tissues. Ithas been suggested that P-glycoprotein in the cell membrane of suchnormal tissues could act to remove toxins or to assist in the transportof nutrients and solutes and to secrete a variety of protein and steroidsubstances. The natural presence of P-glycoprotein in tumor cellsderived from these tissues as well as its presence in tumor cellsderived from other tissue types could explain, at least in part,resistance of various tumors to therapy with standard chemotherapeuticagents. The use of agents which inactivate the P-glycoprotein pump couldbe therapeutic and valuable in the treatment of multi-drug resistanttumors.

SUMMARY OF THE INVENTION

This invention relates to novel diarylalkyl piperidines of Formula 1##STR2## wherein m is an integer selected from the group consisting of0, 1 or 2,

n is an integer selected from the group consisting of 0, 1, 2 or 3,

R₁ and R₂ are each independently selected from the group consisting ofhydrogen, halogen, C₁ -C₄ alkyl or C₁ -C₄ alkoxy, and

Ar is phenyl, optionally substituted with from 1 to 3 substituentsselected from the group consisting of C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁-C₄ alkylthio, halogen, OCH₂ O, CF₃, OCF₃, OH, CN, NO₂, and NH₂ ; andindolyl,

which can be administered with standard chemotherapeutic agents toincrease their effectiveness in the treatment of multi-drug resistanttumors.

DETAILED DESCRIPTION OF THE INVENTION

This invention concerns the use of the compounds of Formula 1 as agentseffective in reversing drug resistance in multi-drug resistant tumors.The compounds of Formula 1 can be administered together with standardchemotherapeutic agents, can be used in the treatment of tumors whichare intrinsically or extrinsically multi-drug resistant, and can be usedto reverse resistance in experimental multi-drug resistant tumor celllines. Multi-drug resistance is defined to be that condition of a tumorcell in which the cell is resistant to a wide variety of unrelatedanticancer drugs such as vinca alkaloids, epipodophyllotoxins,dactinomycin, and anthracycline classes as well as colchicine. (Goodmanand Gilman, 7th Ed., p. 1278.) This broad based, cross resistance candevelop after administration of a single agent of either the vincaalkaloid, epipodophyllotoxins, dactinomycin, and anthracycline classesas well as colchicine and is characterized by resistance to the othermembers of these drug classes. Examples of antitumor drugs of the vincaalkaloid class include the naturally occurring vincristine andvinblastine as well as the synthetic derivative vindesine. Examples ofantitumor drugs of the epipodophyllotoxins class include etoposide andteniposide. An example of an antitumor drug of the anthracycline classis daunorubicin. Examples of antitumor drugs of the dactinomycin classinclude actinomycin A and actinomycin D.

As used herein, the term "(C₁ -C₄)alkoxy" means a straight or branchedchain alkoxy group having from one to four carbon atoms such as methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy,tert-butoxy, and the like.

The compounds of Formula 1 contain one or more asymmetric centers andwill therefore exist as enantiomers and diastereomers. In particular thecarbon atom of the piperidine ring to which the diphenylalkyl group isattached is an asymmetric center. Moreover, when those phenyls aresubstituted, not identically, the carbon atom to which these phenylgroups are attached is an asymmetric center. Any reference to thecompounds of Formula 1, or any intermediate thereof, should be construedas covering a specific optical isomer, a racemic mixture or adiastereometric mixture. The specific optical isomers can be synthesizedor can be separated and recovered by techniques known in the art such aschromatography on chiral stationary phases, resolution via chiral saltformation and subsequent separation by selective crystallization, as isknown in the art. Alternatively, a chirally pure starting material maybe utilized.

The compounds of the present invention can be prepared as described inScheme I. All the substituents, unless otherwise indicated, arepreviously defined. The reagents and starting materials are readilyavailable to one of ordinary skill in the art. ##STR3##

In Scheme I, the appropriately substituted 2-(diphenyl)alkylpiperidinedescribed by structure (1) can be prepared following generally theprocedures disclosed in U.S. Pat. No. 3,252,983, May 24, 1966 and Sury,E. et al., Helv. Chim. Acta., 1954, 2133. The2-(diphenyl)alkylpiperidine can undergo an acylation by treatment withan appropriately substituted acid chloride described by structure (2) toprovide the amide described by Formula 1.

For example, 2-(2,2-diphenyl)ethylpiperidine described by structure (2)wherein m=2 and R₁ and R₂ are hydrogen, is dissolved in a suitableorganic solvent, such as methylene chloride with an excess of a suitabletrialkylamine, such as triethylamine. The solution is then cooled toapproximately 0°-5° C. To this is added dropwise a solution ofapproximately 1.1 equivalents of an appropriately substituted acidchloride described by structure (2), such as3,4,5-trimethoxyphenylacetyl chloride in a suitable organic solvent,such as methylene chloride. The reaction is allowed to warm to roomtemperature and stir for approximately 12 to 24 hours. The desiredproduct described by Formula 1 is then isolated by techniques well knownto one skilled in the art. For example, the reaction is rinsed withdilute hydrochloric acid, followed by water, 5% sodium hydroxide andfinally saturated sodium chloride. The solvent is removed under vacuumand the residue is crystallized from a suitable organic solvent, such asethyl acetate to provide the amide described by Formula 1 wherein m=2,R₁ and R₂ are hydrogen, n=1 and aryl is 3,4,5-tri-methoxyphenyl.

The following examples present typical syntheses as described by SchemeI. These examples are understood to be illustrative only and are notintended to limit the scope of the invention in any way. As used in thefollowing examples, the following terms have the meanings indicated: "g"refers to grams, "mg" refers to milligrams, "mmol" refers to millimoles,"ml" refers to milliliters, and "°C." refers to degrees Celsius.

EXAMPLE 1 ##STR4## Preparation of1-[2-(2,2-Diphenyl-Ethyl)-Piperidin-1-yl]-2-(3,4,5-Trimethoxy-Phenyl)-Ethanone

Scheme I

Cool a solution of triethylamine (1 ml) and2-(2,2-diphenyl)ethylpiperidine (2.65 g, 0.01 moles) in methylenechloride (50 ml), with an ice bath. To this solution add dropwise asolution of 3,4,5-trimethoxyphenylacetyl chloride (2.69 g, 0.011 moles)in methylene chloride (50 ml). Stir the reaction at room temperature for12 hours. Rinse the reaction with dilute hydrochloric acid, water, 5%sodium hydroxide and saturated sodium chloride. Concentrate the organicphase under vacuum and crystallize the residue from ethyl acetate toprovide the title compound, mp 105°-106° C.

Anal. Calcd for C₃₀ H₃₅ NO₄ : C, 76.08; H, 7.45; N, 2.96. Found: C,75.94; H, 7.46; N, 2.88.

EXAMPLE 2 ##STR5## Preparation of1-[2-(2,2-Diphenyl-Ethyl)-Piperidin-1-yl]-2(2-Methoxy-Phenyl)-Ethanone

Scheme I

In an analogous manner to example 1, the title compound is prepared as aviscous oil from excess triethylamine, 2-(2,2-diphenyl)ethylpiperidine(1.0 eq) and 2-methoxyphenylacetyl chloride (1.1 eq).

Anal. Calcd for C₂₈ H₃₁ NO₄ : C, 81.32; H, 7.56; N, 3.39. Found: C,80.81; H, 7.58; N, 3.27.

EXAMPLE 3 ##STR6## Preparation of2-Benzo[1,3]Dioxol-5-yl-1-[2-(2,2-Diphenylethyl)-Piperidin-1-yl]-Ethanone

Scheme I

In an analogous manner to example 1, the title compound, mp 118°-120°C., is prepared from excess triethylamine,2-(2,2-diphenyl)ethylpiperidine (1.0 eq) and3,4-(methylenedioxy)phenylacetyl chloride (1.1 eq).

Anal. Calcd for C₂₈ H₂₉ NO₃ : C, 78.66; H, 6.84; N, 3.28. Found: C,78.51; H, 6.71; N, 3.27.

EXAMPLE 4 ##STR7## Preparation of1-[2-(2,2-Diphenyl-Ethyl)-Piperidin-1-yl]-2-(3,4-Dimethoxy-Phenyl)-Ethanone

Scheme I

In an analogous manner to Example 1, the title compound, mp 113°-114°C., is prepared from excess triethylamine,2-(2,2-diphenyl)ethylpiperidine (1.0 eq) and 3,4-dimethoxyphenylacetylchloride (1.1 eq).

Anal. Calcd for C₂₉ H₃₃ NO₃ : C, 78.52; H, 7.50; N, 3.16. Found: C,78.21; H, 7.60; N, 3.01.

EXAMPLE 5 ##STR8## Preparation of2-(3,4-Dichloro-Phenyl)-1-[2-(2,2-diphenylethyl)-Piperidin-1-yl]-Ethanone

Scheme I

In an analogous manner to Example 1, the title compound, mp 82°-84° C.,is prepared from excess triethylamine, 2-(2,2-diphenyl)ethylpiperidine(1.0 eq) and 3,4-dichlorophenylacetyl chloride (1.1 eq).

Anal. Calcd for C₂₇ H₂₇ Cl₂ No: C, 71.68; H, 6.02; N, 3.10 5 Found: C,71.60; H, 6.16; N, 3.04.

EXAMPLE 6 ##STR9## Preparation of3-(3,4-Dimethoxy-Phenyl)-1-[2-(2,2-Diphenylethyl)-Piperidin-1-yl]-Propan-1-one

Scheme I

In an analogous manner to Example 1, the title compound, mp 138°-139°C., is prepared from excess triethylamine,2-(2,2-diphenyl)ethylpiperidine (1.0 eq) and3-(3,4-dimethoxyphenyl)propionyl chloride (1.1 eq).

Anal. Calcd for C₃₀ H₃₅ NO₃ : C, 78.74; H, 7.71; N, 3.06. Found: C,78.49; H, 7.86; N, 2.87.

EXAMPLE 7 ##STR10## Preparation of1-[2-(2,2-Di-p-Tolyl-Ethyl)-Piperidin-1-yl]2-(3,4,5-Trimethoxy-Phenyl)-Ethanone

Scheme I

In an analogous manner to Example 1, the title compound, mp 98°-100° C.,is prepared from excess triethylamine,2-(2,2-(4,4'-ditoluoyl)ethylpiperidine (1.0 eq) and3,4,5-trimethoxyphenylacetyl chloride (1.1 eq).

Anal. Calcd for C₃₂ H₃₉ NO₄ : C, 76.62; H, 7.84; N, 2.79. Found: C,76.38; H, 7.84; N, 2.71.

EXAMPLE 8 ##STR11## Preparation of1-[2-(2,2-Diphenyl-Ethyl)-Piperidin-1-yl]-2(1H-Indol-3-yl)-Ethanone

Scheme I

In an analogous manner to Example 1, the title compound, mp 180°-181°C., is prepared from excess triethylamine,2-(2,2-diphenyl)ethylpiperidine (1.0 eq) and indole-3-acetyl chloride(1.1 eq).

Anal. Calcd for C₂₉ H₃₀ N₂ O: C, 82.43; H, 7.16; N, 6.63. Found: C,82.56; H, 7.18; N, 6.56.

EXAMPLE 9 ##STR12## Preparation of1-[2-Diphenylmethyl)-Piperidin-1-yl]-2(3,4,5-Trimethoxy-Phenyl)-Ethanone

Scheme I

In an analogous manner to Example 1, the title compound, mp 122°-124°C., is prepared from excess triethylamine, 2-diphenylmethylpiperidine(1.0 eq) and 3,4,5-trimethoxyphenylacetyl chloride (1.1 eq).

Anal. Calcd for C₂₉ H₃₃ NO₄ : C, 75.79; H, 7.24; N, 3.05. Found: C,75.52; H, 7.33; N, 2.98.

DETERMINATION OF MDR ACTIVITY

A colorimetric assay is employed to determine the synergy between testcompounds of the invention and vinblastine or adriamycin against thegrowth of MDR tumor cells. The assay is based on the ability of livetumor cells to reduce a tetrazoline compound, MTT(3-(4,5-dimethyl)imazol-2-yl)-2,5-diphenyl tetrazolium bromide, to ablue formazan product. Both the test compound and cytotoxic drug(vinblastine or adriamycin) were added to the cells growing in wells ofa 96-well plate at different combinations of concentration. The cellswere allowed to grow for 72 hr and, at the end of incubation, stainedwith MTT for 3 hr. The blue formazan product which developed, wasdissolved with DMSO and the color intensity was recorded in aspectrophotometer. Based on the data, an isobologram analysis wasperformed. MDR activity (ED₅₀ : μM) represents the concentration of thecompound required to lower the IC₅₀ value of vinblastine by 50% whenboth the compounds were added to the medium together. Cellular toxicity(IC₅₀ : μM) represents concentration of the compound that inhibit cellgrowth by 50%. Activity index is the ratio of toxicity and MDR activity.

                  TABLE 1                                                         ______________________________________                                        MDR ACTIVITY OF DIARYLALKYL PIPERIDINES                                        ##STR13##                                                                                           MDR Activity                                                                            Toxicity                                                                             Activity                              Ar        m      n     ED.sub.50 μM                                                                         (IC50 μM                                                                          Index                                 ______________________________________                                        .O slashed. 3,4,5-(OCH.sub.3).sub.3                                                     1      1     0.31      33.8   109.0                                 .O slashed. 3,4-(OCH.sub.3).sub.2                                                       1      2     0.46      21.6   47.0                                  .O slashed. 3,4,5-OCH.sub.3                                                             0      1     0.70      30.3   43.5                                  .O slashed. 3,4-(OCH.sub.2 O)                                                           1      1     1.20      39.0   32.5                                  .O slashed. 2-OCH.sub.3                                                                 1      1     1.16      37.5   32.0                                  ______________________________________                                    

The term "patient" used herein is taken to mean mammals such asprimates, including humans, and animals such as sheep, horses, cattle,pigs, dogs, cats, rats and mice.

The amount of the diarylalkyl piperidine derivative of Formula 1 to beadministered can vary widely according to the particular dosage unitemployed, the period of treatment, the age and sex of the patienttreated, the nature and extent of the multi-drug resistance in the tumorto be treated, and the particular diarylalkyl piperidine derivativeselected. The diarylalkyl piperidine derivative is used in conjunctionwith other chemotherapeutic agents known to be useful in the treatmentof tumors. The amount of a diarylalkyl piperidine derivative of Formula1 effective to reverse multi-drug resistance will generally range fromabout 15 mg/kg to 500 mg/kg. A unit dosage may contain from 25 to 500 mgof the diarylalkyl piperidine derivative, and can be taken one or moretimes per day. The diarylalkyl piperidine derivative can be administeredwith a pharmaceutical carrier using conventional dosage unit formseither orally or parenterally.

Treatment of tumors by the method of this invention requires that anantitumor effective amount of a chemotherapeutic agent be administeredtogether with a compound of Formula 1. Tumors which can be treated bythe method of this invention include both benign and malignant tumors orneoplasms, and include melanomas, lymphomas, leukemias, and sarcomas.Illustrative examples of tumors are cutaneous tumors, such as malignantmelanomas and mycosis fungoids; hematologic tumors such as ieukemias,for example, acute lymphoblastic, acute myelocytic or chronic myelocyticleukemia; lymphomas, such as Hodgkin's disease or malignant lymphoma;gynecologic tumors, such as ovarian and uterine tumors; urologic tumors,such as those of the prostate, bladder or testis; soft tissue sarcomas,osseous or non-osseous sarcomas, breast tumors; tumors of the pituitary,thyroid and adrenal cortex; gastrointestinal tumors, such as those ofthe esophagus, stomach, intestine and colon; pancreatic and hepatictumors; laryngeal papillomestasas and lung tumors. Of course thosetumors which typically are or become multi-drug resistant are mostbeneficially treated with the compounds and methods of this invention.Such tumors include colon tumors, lung tumors, stomach tumors, and livertumors.

The chemotherapeutic agents used together with the diarylalkylpiperidines of Formula 1 are those cytotoxic agents commonly used in thetreatment of tumors. Illustrative examples of chemotherapeutic agentsare: cyclophosphamide, methotrexate, prednisone, 6-mercaptopurine,procarbazine, daunorubicin, vincristine, vinblastine, chlorambucil,cytosine arabinoside, 6-thioguanine, thio TEPA, 5-fluorouracil,5-fluoro-2deoxyudirinde, 5-azacytidine, nitrogen mustard,1,3-bis(2chloroethyl)-1-nitrosourea (BCNU),(1-(2-chloroethyl)-3cyclohexyl-1-nitrosourea) (CCNU), busulfan,adriamycin, bleomycin, vindesine, cycloleucine or methylglyoxalbis(guanylhydrazone) (i.e., MGBG). The effective amount ofchemotherapeutic agent used in the method of this invention varieswidely and depends on factors such as the patient, the tumor tissue typeand its size, and the particular chemotherapeutic agent selected. Theamount is any effective amount and can be readily determined by thoseskilled in the art. In general, less chemotherapeutic agent will berequired when administered with the diarylalkyl piperidines of Formula1, primarily because the problem of drug resistance need not addressedby the addition of larger quantities of chemotherapeutic agent. Ofcourse mixtures of chemotherapeutic agents may be employed and surgicalexcision and radiation therapy may be useful adjuvants as in any tumortherapy. While the compound of Formula 1 and the chemotherapeutic agentare said to be administered together, this does not necessarily meanthat the compounds are formulated into the same dosage form or areadministered concurrently. Rather, the expression "together" means thata compound of Formula 1 and the chemotherapeutic agent(s) areadministered in a combined dosage form or separately during the courseof therapy.

The preferred route of administration is oral administration. For oraladministration the derivative can be formulated into solid or liquidpreparations such as capsules, pills, tablets, troches, lozenges, melts,powders, solutions, suspensions, or emulsions. The solid unit dosageforms can be a capsule which can be of the ordinary hard- orsoft-shelled gelatin type containing, for example, surfactants,lubricants, and inert fillers such as lactose, sucrose, calciumphosphate, and cornstarch. In another embodiment the compounds of thisinvention can be tableted with conventional tablet bases such aslactose, sucrose, and cornstarch in combination with binders such asacacia, cornstarch, or gelatin, disintegrating agents intended to assistthe breakup and dissolution of the tablet following administration suchas potato starch, alginic acid, corn starch, and guar gum, lubricantsintended to improve the flow of tablet granulations and to prevent theadhesion of tablet material to the surfaces of the tablet dies andpunches, for example, talc, stearic acid, or magnesium, calcium, or zincstearate, dyes, coloring agents, and flavoring agents intended toenhance the esthetic qualities of the tablets and make them moreacceptable to the patient. Suitable excipients for use in oral liquiddosage forms include diluents such as water and alcohols, for example,ethanol, benzyl alcohol, and the polyethylene alcohols, either with orwithout the addition of a pharmaceutically acceptably surfactant,suspending agent, or emulsifying agent.

The diarylalkyl piperidine derivatives of this invention may also beadministered parenterally, that is, subcutaneously, intravenously,intramuscularly, or interperitoneally, as injectable dosages of thecompound in a physiologically acceptable diluent with a pharmaceuticalcarrier which can be a sterile liquid or mixture of liquids such aswater, saline, aqueous dextrose and related sugar solutions, an alcoholsuch as ethanol, isopropanol, or hexadecyl alcohol, glycols such aspropylene glycol or polyethylene glycol, glycerol ketals such as2,2-dimethyl-1,3-dioxolane-4-methanol, ethers such as polyethyleneglycol400, an oil, a fatty acid, a fatty acid ester or glyceride, or anacetylated fatty acid glyceride with or without the addition of apharmaceutically acceptable surfactant such as a soap or a detergent,suspending agent such as pectin, carbomers, methylcellulose,hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifyingagent and other pharmaceutically adjuvants. Illustrative of oils whichcan be used in the parenteral formulations of this invention are thoseof petroleum, animal, vegetable, or synthetic origin, for example,peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, oliveoil, petrolatum, and mineral oil. Suitable fatty acids include oleicacid, stearic acid, and isostearic acid. Suitable fatty acid esters are,for example, ethyl oleate and isopropyl myristate. Suitable soapsinclude fatty alkali metal, ammonium, and triethanolamine salts andsuitable detergents include cationic detergents, for example, dimethyldialkyl ammonium halides, alkyl pyridinium halides, and alkylaminesacetates; anionic detergents, for example, alkyl, aryl, and olefinsulfonates, alkyl, olefin, ether, and monoglyceride sulfates, andsulfosuccinates; nonionic detergents, for example, fatty amine oxides,fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers;and amphoteric detergents, for example, alkyl-β-aminopropionates, and2-alkylimidazoline quaternary ammonium salts, as well as mixtures. Theparenteral compositions of this invention will typically contain fromabout 0.5 to about 25% by weight of the oxazolone derivative of Formula1 in solution. Preservatives and buffers may also be usedadvantageously.

In order to minimize or eliminate irritation at the site of injection,the compounds of this invention can also be administered topically. Thiscan be accomplished by simply preparing a solution of the compound to beadministered, preferably using a solvent known to promote transdermalabsorption such as ethanol or dimethyl sulfoxide (DMSO) with or withoutother excipients.

Preferably topical administration will be accomplished using a patcheither of the reservoir and porous membrane type or of a solid matrixvariety. Some suitable transdermal devices are described in U.S. Pat.Nos. 3,742,951, 3,797,494, 3,996,934, and 4,031,894. These devicesgenerally contain a backing member which defines one of its facesurfaces, an active agent permeable adhesive layer defining the otherface surface and at least one reservoir containing the active agentinterposed between the face surfaces. Alternatively, the active agentmay be contained in a plurality of microcapsules distributed throughoutthe permeable adhesive layer. In either case, the active agent isdelivered continuously from the reservoir or microcapsules through amembrane into the active agent permeable adhesive, which is in contactwith the skin or mucosa of the recipient. If the active agent isabsorbed through the skin, a controlled and predetermined flow of theactive agent is administered to the recipient. In the case ofmicrocapsules, the encapsulating agent may also function as themembrane.

In another device for transdermally administering the compounds inaccordance with the present invention, the pharmaceutically activecompound is contained in a matrix from which it is delivered in thedesired gradual, constant and controlled rate. The matrix is permeableto the release of the compound through diffusion or microporous flow.The release is rate controlling. Such a system, which requires nomembrane is described in U.S. Pat. No. 3,921,636. At least two types ofrelease are possible in these systems. Release by diffusion occurs whenthe matrix is nonporous. The pharmaceutically effective compounddissolves in and diffuses through the matrix itself. Release bymicroporous flow occurs when the pharmaceutically effective compound istransported through a liquid phase in the pores of the matrix.

What is claimed is:
 1. A method of reversing drug resistance inmulti-drug resistant tumors by administering to a patient in need ofsuch treatment an effective amount of a compound of the formula##STR14## wherein m is an integer selected from the group consisting of0, 1 or 2, n is an integer selected from the group consisting of 0, 1, 2or 3,R₁ and R₂ are each independently selected from the group consistingof hydrogen, halogen, C₁ -C₄ alkyl or C₁ -C₄ alkoxy, and Ar is phenyloptionally substituted with from 1 to 3 substituents selected from thegroup consisting of C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₁ -C₄ alkylthio,halogen, OCH₂ O, CF₃, OCF₃, OH, CN, NO₂, and NH₂ ; or indolyl.
 2. Amethod according to claim 1 wherein m and n are 1, Ar is3,4,5-trimethoxphenyl, and R₁ and R₂ are hydrogen.
 3. A method accordingto claim 1 wherein m and n are 1, Ar is 3,4-methylenedioxyphenyl, and R₁and R₂ are hydrogen.
 4. A method according to claim 1 wherein m is 1, nis 2, Ar is 3,4-dimethoxyphenyl, and R₁ and R₂ are hydrogen.
 5. A methodaccording to claim 1 wherein m is 0, n is 1, Ar id3,4,5-trimethoxyphenyl, and R₁ and R₂ are hydrogen.
 6. A methodaccording to claim 1 wherein m and n are 1, Ar is 2-methoxyphenyl, andR₁ and R₂ are hydrogen.